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Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization.
Bone. 2021 01; 142:115656.BONE

Abstract

Ectonucleotide phosphatase/phosphodiesterase 1 (ENPP1) deficiency results in either lethal arterial calcifications ('Generalized Arterial Calcification of Infancy' - GACI), phosphate wasting rickets ('Autosomal Recessive Hypophosphatemic Rickets type 2' - ARHR2), early onset osteoporosis, or progressive spinal rigidity ('Ossification of the Posterior Longitudinal Ligament' - OPLL). As ENPP1 generates a strong endogenous mineralization inhibitor - extracellular pyrophosphate (PPi) - ENPP1 deficiency should not result in reduced bone volume, and therefore the mechanism ENPP1 associated osteoporosis is not apparent given current understanding of the enzyme's function. To investigate genetic pathways driving the skeletal phenotype of ENPP1 deficiency we compared gene expression in Enpp1asj/asj mice and WT sibling pairs by RNAseq and qPCR in whole bones, and in the liver and kidney by qPCR, directly correlating gene expression with measures of bone microarchitectural and biomechanical phenotypes. Unbiased analysis of the differentially expressed genes compared to relevant human disease phenotypes revealed that Enpp1asj/asj mice exhibit strong signatures of osteoporosis, ARHR2 and OPLL. We found that ENPP1 deficient mice exhibited reduced gene transcription of Wnt ligands in whole bone and increased transcription of soluble Wnt inhibitors in the liver and kidney, suggestive of multiorgan inhibition of Wnt activity. Consistent with Wnt suppression in bone, Collagen gene pathways in bone were significantly decreased and Fgf23 was significantly increased, all of which directly correlated with bone microarchitectural defects and fracture risk in Enpp1asj/asj mice. Moreover, the bone findings in 10-week old mice correlated with Enpp1 transcript counts but not plasma [PPi], suggesting that the skeletal phenotype at 10 weeks is driven by catalytically independent ENPP1 function. In contrast, the bone findings in 23-week Enpp1asj/asj mice strongly correlated with plasma PPi, suggesting that chronically low PPi drives the skeletal phenotype in older mice. Finally, correlation between Enpp1 and Fgf23 transcription suggested ENPP1 regulation of Fgf23, which we confirmed by dosing Enpp1asj/asj mice with soluble ENPP1-Fc and observing suppression of intact plasma FGF23 and ALP. In summary, our findings suggest that osteoporosis associated with ENPP1 deficiency involves the suppression of Wnt via catalytically independent Enpp1 pathways, and validates Enpp1asj/asj mice as tools to better understand OPLL and Paradoxical Mineralization Disorders.

Authors+Show Affiliations

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.Department of Pediatrics at Yale University School of Medicine, New Haven, CT 06510, USA.Department of Biology and Chemistry, California State University, Monterey Bay, CA, USA. Electronic address: njue@csumb.edu.Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: demetrios.braddock@yale.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

32980560

Citation

Maulding, Nathan D., et al. "Genetic Pathways Disrupted By ENPP1 Deficiency Provide Insight Into Mechanisms of Osteoporosis, Osteomalacia, and Paradoxical Mineralization." Bone, vol. 142, 2021, p. 115656.
Maulding ND, Kavanagh D, Zimmerman K, et al. Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. Bone. 2021;142:115656.
Maulding, N. D., Kavanagh, D., Zimmerman, K., Coppola, G., Carpenter, T. O., Jue, N. K., & Braddock, D. T. (2021). Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. Bone, 142, 115656. https://doi.org/10.1016/j.bone.2020.115656
Maulding ND, et al. Genetic Pathways Disrupted By ENPP1 Deficiency Provide Insight Into Mechanisms of Osteoporosis, Osteomalacia, and Paradoxical Mineralization. Bone. 2021;142:115656. PubMed PMID: 32980560.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. AU - Maulding,Nathan D, AU - Kavanagh,Dillon, AU - Zimmerman,Kristin, AU - Coppola,Gianfilippo, AU - Carpenter,Thomas O, AU - Jue,Nathaniel K, AU - Braddock,Demetrios T, Y1 - 2020/09/24/ PY - 2020/03/31/received PY - 2020/09/17/revised PY - 2020/09/18/accepted PY - 2022/01/01/pmc-release PY - 2020/9/28/pubmed PY - 2021/6/22/medline PY - 2020/9/27/entrez KW - Autosomal Recessive Hypophosphatemic Rickets (ARHR2) KW - ENPP1 KW - FGF23 KW - Generalized Arterial Calcification of Infancy (GACI) KW - Ossification of the Posterior Longitudinal Ligament (OPLL) KW - Osteoporosis KW - Paradoxical mineralization KW - Pyrophosphate KW - RNASeq KW - Rare bone diseases SP - 115656 EP - 115656 JF - Bone JO - Bone VL - 142 N2 - Ectonucleotide phosphatase/phosphodiesterase 1 (ENPP1) deficiency results in either lethal arterial calcifications ('Generalized Arterial Calcification of Infancy' - GACI), phosphate wasting rickets ('Autosomal Recessive Hypophosphatemic Rickets type 2' - ARHR2), early onset osteoporosis, or progressive spinal rigidity ('Ossification of the Posterior Longitudinal Ligament' - OPLL). As ENPP1 generates a strong endogenous mineralization inhibitor - extracellular pyrophosphate (PPi) - ENPP1 deficiency should not result in reduced bone volume, and therefore the mechanism ENPP1 associated osteoporosis is not apparent given current understanding of the enzyme's function. To investigate genetic pathways driving the skeletal phenotype of ENPP1 deficiency we compared gene expression in Enpp1asj/asj mice and WT sibling pairs by RNAseq and qPCR in whole bones, and in the liver and kidney by qPCR, directly correlating gene expression with measures of bone microarchitectural and biomechanical phenotypes. Unbiased analysis of the differentially expressed genes compared to relevant human disease phenotypes revealed that Enpp1asj/asj mice exhibit strong signatures of osteoporosis, ARHR2 and OPLL. We found that ENPP1 deficient mice exhibited reduced gene transcription of Wnt ligands in whole bone and increased transcription of soluble Wnt inhibitors in the liver and kidney, suggestive of multiorgan inhibition of Wnt activity. Consistent with Wnt suppression in bone, Collagen gene pathways in bone were significantly decreased and Fgf23 was significantly increased, all of which directly correlated with bone microarchitectural defects and fracture risk in Enpp1asj/asj mice. Moreover, the bone findings in 10-week old mice correlated with Enpp1 transcript counts but not plasma [PPi], suggesting that the skeletal phenotype at 10 weeks is driven by catalytically independent ENPP1 function. In contrast, the bone findings in 23-week Enpp1asj/asj mice strongly correlated with plasma PPi, suggesting that chronically low PPi drives the skeletal phenotype in older mice. Finally, correlation between Enpp1 and Fgf23 transcription suggested ENPP1 regulation of Fgf23, which we confirmed by dosing Enpp1asj/asj mice with soluble ENPP1-Fc and observing suppression of intact plasma FGF23 and ALP. In summary, our findings suggest that osteoporosis associated with ENPP1 deficiency involves the suppression of Wnt via catalytically independent Enpp1 pathways, and validates Enpp1asj/asj mice as tools to better understand OPLL and Paradoxical Mineralization Disorders. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/32980560/Genetic_pathways_disrupted_by_ENPP1_deficiency_provide_insight_into_mechanisms_of_osteoporosis_osteomalacia_and_paradoxical_mineralization_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(20)30436-1 DB - PRIME DP - Unbound Medicine ER -